Broad-Spectrum Bactericidal Activity of a Synthetic Random Copolymer Based on 2-Methoxy-6-(4-Vinylbenzyloxy)-Benzylammonium Hydrochloride.

Anna Maria Schito,Gabriela Piatti,Silvana Alfei,Guendalina Zuccari,Debora Caviglia

doi:10.3390/ijms22095021

Anna Maria Schito, Gabriela Piatti + Show 3 more

Open Access

https://doi.org/10.3390/ijms22095021

Copy DOI

Abstract

Low-molecular-weight organic ammonium salts exert excellent antimicrobial effects by interacting lethally with bacterial membranes. Unfortunately, short-term functionality and high toxicity limit their clinical application. On the contrary, the equivalent macromolecular ammonium salts, derived from the polymerization of monomeric ammonium salts, have demonstrated improved antibacterial potency, a lower tendency to develop resistance, higher stability, long-term activity, and reduced toxicity. A water-soluble non-quaternary copolymeric ammonium salt (P7) was herein synthetized by copolymerizing 2-methoxy-6-(4-vinylbenzyloxy)-benzylammonium hydrochloride monomer with N, N-di-methyl-acrylamide. The antibacterial activity of P7 was assessed against several multidrug-resistant (MDR) clinical isolates of both Gram-positive and Gram-negative species. Except for colistin-resistant Pseudomonas aeruginosa, most isolates were susceptible to P7, also including some Gram-negative bacteria with a modified charge in the external membrane. P7 showed remarkable antibacterial activity against isolates of Enterococcus, Staphylococcus, Acinetobacter, and Pseudomonas, and on different strains of Escherichia coli and Stenotrophomonas maltophylia, regardless of their antibiotic resistance. The lowest minimal inhibitory concentrations (MICs) observed were 0.6–1.2 µM and the minimal bactericidal concentrations (MBC) were frequently overlapping with the MICs. In 24-h time–kill and turbidimetric studies, P7 displayed a rapid non-lytic bactericidal activity. P7 could therefore represent a novel and potent tool capable of counteracting infections sustained by several bacteria that are resistant to the presently available antibiotics.

Highlights

Small-molecular-weight quaternary ammonium salts (QASs), such as the well-known benzalkonium hydrochloride, commercially available as CITROSIL® [1], and several of its derivatives, have been broadly studied and intensively used as antimicrobial agents, endowed with considerable broad-spectrum potency against Gram-positive and Gramnegative bacteria and some fungi [2]
The side effects caused by the topical application of QASs are relatively moderate in comparison to those derived from systemic administrations [5], a number of limitations concerning the topical use of low-molecular-weight QASs have become noticeable
Of the 23 Gram-positive organisms tested, ten strains belonged to the Enterococcus genus, (four Enterococcus faecalis (resistant to vancomycin (VRE)), three E. faecium vancomycin resistance (VRE), one E. casseliflavus, and one E.durans and one E. gallinarum); 12 strains pertained to the Staphylococcus genus, including two methicillin-resistant S. auresus (MRSA) and one susceptible, three methicillin-resistant S. epidermidis (MRSE), two of which were resistant to linezolid, one methicillin-resistant (MR) S. haemolyticus, one S. hominis MR, one S. lugdunensis, one S. sapropyticus, one S. simulans MR, and one S. warneri

Summary

Introduction

Small-molecular-weight quaternary ammonium salts (QASs), such as the well-known benzalkonium hydrochloride, commercially available as CITROSIL® [1], and several of its derivatives, have been broadly studied and intensively used as antimicrobial agents, endowed with considerable broad-spectrum potency against Gram-positive and Gramnegative bacteria and some fungi [2]. After absorption on the bacterial surface, intercalating with the membranes and altering their normal structure, QASs cause the formation of pores, modifying membranes’ permeability, causing the loss of enzymes, coenzymes, and ions. Due to these events, QASs compromise the biosynthetic activities of bacteria, triggering their death [2]. QASs’ non-specific antimicrobial mechanism translates into low selectivity for pathogens, significant toxicity toward eukaryotic cells, and hemolytic toxicity [2,3,4] These drawbacks significantly hamper their administration in vivo by the oral route and/or intravenous injection, limiting their use as surface disinfectants and in epidermal treatment [2]. The side effects caused by the topical application of QASs are relatively moderate in comparison to those derived from systemic administrations [5], a number of limitations concerning the topical use of low-molecular-weight QASs have become noticeable

Objectives

Methods

Results

Conclusion